Open-source versatile 3D-print animal conditioning platform design for in vivo preclinical brain imaging in awake mice and anesthetized mice and rats.

Proper animal conditioning is a key factor in the quality and success of preclinical neuroimaging applications. Here, we introduce an open-source easy-to-modify multimodal 3D printable design for rodent conditioning for magnetic resonance imaging (MRI) or other imaging modalities. Our design can be used for brain imaging in anesthetized or awake mice, and in anesthetized rats. We show ease of use and reproducibility of subject conditioning with anatomical T2-weighted imaging for both mice and rats. We also demonstrate the application of our design for awake functional MRI in mice using both visual evoked potential and olfactory stimulation paradigms. In addition, using a combined MRI, positron emission tomography and X-ray computed tomography experiment, we demonstrate that our proposed cradle design can be utilized for multiple imaging modalities.

Autonomous animal heating and cooling system for temperature-regulated magnetic resonance experiments.

Temperature is a hallmark parameter influencing almost all magnetic resonance properties (e.g., T1 , T2 , proton density, and diffusion). In the preclinical setting, temperature has a large influence on animal physiology (e.g., respiration rate, heart rate, metabolism, and oxidative stress) and needs to be carefully regulated, especially when the animal is under anesthesia and thermoregulation is disrupted. We present an open-source heating and cooling system capable of regulating the temperature of the animal. The system was designed using Peltier modules capable of heating or cooling a circulating water bath with active temperature feedback. Feedback was obtained using a commercial thermistor, placed in the animal rectum, and a proportional-integral-derivative controller was used to modulate the temperature. Its operation was demonstrated in a phantom as well as in mouse and rat animal models, where the standard deviation of the temperature of the animal upon convergence was less than a 10th of a degree. An application where brain temperature of a mouse was modulated was demonstrated using an invasive optical probe and noninvasive magnetic resonance spectroscopic thermometry measurements.

Brain-implanted conductors amplify radiofrequency fields in rodents: Advantages and risks.

Over the past few decades, daily exposure to radiofrequency (RF) fields has been increasing due to the rapid development of wireless and medical imaging technologies. Under extreme circumstances, exposure to very strong RF energy can lead to heating of body tissue, even resulting in tissue injury. The presence of implanted devices, moreover, can amplify RF effects on surrounding tissue. Therefore, it is important to understand the interactions of RF fields with tissue in the presence of implants, in order to establish appropriate wireless safety protocols, and also to extend the benefits of medical imaging to increasing numbers of people with implanted medical devices. This study explored the neurological effects of RF exposure in rodents implanted with neuronal recording electrodes. We exposed freely moving and anesthetized rats and mice to 950 MHz RF energy while monitoring their brain activity, temperature, and behavior. We found that RF exposure could induce fast onset firing of single neurons without heat injury. In addition, brain implants enhanced the effect of RF stimulation resulting in reversible behavioral changes. Using an optical temperature measurement system, we found greater than tenfold increase in brain temperature in the vicinity of the implant. On the one hand, our results underline the importance of careful safety assessment for brain-implanted devices, but on the other hand, we also show that metal implants may be used for neurostimulation if brain temperature can be kept within safe limits.

An experimental system for detection and localization of hemorrhage using ultra-wideband microwaves with deep learning.

Stroke is a leading cause of mortality and disability. Emergent diagnosis and intervention are critical, and predicated upon initial brain imaging; however, existing clinical imaging modalities are generally costly, immobile, and demand highly specialized operation and interpretation. Low-energy microwaves have been explored as low-cost, small form factor, fast, and safe probes of tissue dielectric properties, with both imaging and diagnostic potential. Nevertheless, challenges inherent to microwave reconstruction have impeded progress, hence microwave imaging (MWI) remains an elusive scientific aim. Herein, we introduce a dedicated experimental framework comprising a robotic navigation system to translate blood-mimicking phantoms within an anatomically realistic human head model. An 8-element ultra-wideband (UWB) array of modified antipodal Vivaldi antennas was developed and driven by a two-port vector network analyzer spanning 0.6-9.0 GHz at an operating power of 1 mw. Complex scattering parameters were measured, and dielectric signatures of hemorrhage were learned using a dedicated deep neural network for prediction of hemorrhage classes and localization. An overall sensitivity and specificity for detection >0.99 was observed, with Rayliegh mean localization error of 1.65 mm. The study establishes the feasibility of a robust experimental model and deep learning solution for UWB microwave stroke detection.

In-vivo measurement of radio frequency electric fields in mice brain.

With the development of novel technologies, radio frequency (RF) energy exposure is expanding at various wavelengths and power levels. These developments necessitate updated approaches of RF measurements in complex environments, particularly in live biological tissue. Accurate dosimetry of the absorbed RF electric fields (E-Fields) by the live tissue is the keystone of environmental health considerations for this type of ever-growing non-ionizing radiation energy. In this study, we introduce a technique for direct in-vivo measurement of electric fields in living tissue. Proof of principle in-vivo electric field measurements were conducted in rodent brains using Bismuth Silicon Oxide (BSO) crystals exposed to varying levels of RF energy. Electric field measurements were calibrated and verified using in-vivo temperature measurements using optical temperature fibers alongside electromagnetic field simulations of a transverse electromagnetic (TEM) cell.

Autonomous animal heating and cooling system for temperature-regulated MR experiments.

Temperature is a hallmark parameter influencing almost all magnetic resonance properties (e.g., T\textsubscript{1}, T\textsubscript{2}, proton density, diffusion and more). In the pre-clinical setting, temperature has a large influence on animal physiology (e.g., respiration rate, heart rate, metabolism, cellular stress, and more) and needs to be carefully regulated, especially when the animal is under anesthesia and thermoregulation is disrupted. We present an open-source heating and cooling system capable of stabilizing the temperature of the animal. The system was designed using Peltier modules capable of heating or cooling a circulating water bath with active temperature feedback. Feedback was obtained using a commercial thermistor, placed in the animal rectum, and a proportional{\text -}integral{\text -}derivative (PID) controller capable of locking the temperature. Operation was demonstrated in a phantom as well as mouse and rat animal models, where the standard deviation of the temperature of the animal upon convergence was less than a tenth of a degree. An application where brain temperature of a mouse was modulated was demonstrated using an invasive optical probe and non-invasive magnetic resonance spectroscopic thermometry measurements.

Quadrupolar 23Na+ NMR relaxation as a probe of subpicosecond collective dynamics in aqueous electrolyte solutions.

Nuclear magnetic resonance relaxometry represents a powerful tool for extracting dynamic information. Yet, obtaining links to molecular motion is challenging for many ions that relax through the quadrupolar mechanism, which is mediated by electric field gradient fluctuations and lacks a detailed microscopic description. For sodium ions in aqueous electrolytes, we combine ab initio calculations to account for electron cloud effects with classical molecular dynamics to sample long-time fluctuations, and obtain relaxation rates in good agreement with experiments over broad concentration and temperature ranges. We demonstrate that quadrupolar nuclear relaxation is sensitive to subpicosecond dynamics not captured by previous models based on water reorientation or cluster rotation. While ions affect the overall water retardation, experimental trends are mainly explained by dynamics in the first two solvation shells of sodium, which contain mostly water. This work thus paves the way to the quantitative understanding of quadrupolar relaxation in electrolyte and bioelectrolyte systems.

Neuronal activity under transcranial radio-frequency stimulation in metal-free rodent brains in-vivo.

As the use of Radio Frequency (RF) technologies increases, the impact of RF radiation on neurological function continues to receive attention. Whether RF radiation can modulate ongoing neuronal activity by non-thermal mechanisms has been debated for decades. However, the interactions between radiated energy and metal-based neural probes during experimentation could impact neural activity, making interpretation of the results difficult. To address this problem, we modified a miniature 1-photon Ca2+ imaging device to record interference-free neural activity and compared the results to those acquired using metal-containing silicon probes. We monitored the neuronal activity of awake rodent-brains under RF energy exposure (at 950 MHz) and in sham control paradigms. Spiking activity was reliably affected by RF energy in metal containing systems. However, we did not observe neuronal responses using metal-free optical recordings at induced local electric field strengths up to 230 V/m. Our results suggest that RF exposure higher than levels that are allowed by regulatory limits in real-life scenarios do not affect neuronal activity.

A stroke detection and discrimination framework using broadband microwave scattering on stochastic models with deep learning.

Stroke poses an immense public health burden and remains among the primary causes of death and disability worldwide. Emergent therapy is often precluded by late or indeterminate times of onset before initial clinical presentation. Rapid, mobile, safe and low-cost stroke detection technology remains a deeply unmet clinical need. Past studies have explored the use of microwave and other small form-factor strategies for rapid stroke detection; however, widespread clinical adoption remains unrealized. Here, we investigated the use of microwave scattering perturbations from ultra wide-band antenna arrays to learn dielectric signatures of disease. Two deep neural networks (DNNs) were used for: (1) stroke detection ("classification network"), and (2) characterization of the hemorrhage location and size ("discrimination network"). Dielectric signatures were learned on a simulated cohort of 666 hemorrhagic stroke and control subjects using 2D stochastic head models. The classification network yielded a stratified K-fold stroke detection accuracy > 94% with an AUC of 0.996, while the discrimination network resulted in a mean squared error of < 0.004 cm and < 0.02 cm, for the stroke localization and size estimation, respectively. We report a novel approach to intelligent diagnostics using microwave wide-band scattering information thus circumventing conventional image-formation.

Multinuclear absolute magnetic resonance thermometry.

Non-invasive measurement of absolute temperature is important for proper characterization of various pathologies and for evaluation of thermal dose during interventional procedures. The proton (hydrogen nucleus) magnetic resonance (MR) frequency shift method can be used to map relative temperature changes. However, spatiotemporal variations in the main magnetic field and the lack of local internal frequency reference challenge the determination of absolute temperature. Here, we introduce a multinuclear method for absolute MR thermometry, based on the fact that the hydrogen and sodium nuclei exhibit a unique and distinct characteristic frequency dependence with temperature and with electrolyte concentration. A one-to-one mapping between the precession frequency difference of the two nuclei and absolute temperature is demonstrated. Proof-of-concept experiments were conducted in aqueous solutions with different NaCl concentrations, in agarose gel samples, and in freshly excised ex vivo mouse tissues. One-dimensional chemical shift imaging experiments also demonstrated excellent agreement with infrared measurements.

Synthesized tissue-equivalent dielectric phantoms using salt and polyvinylpyrrolidone solutions.

PURPOSE: To explore the use of polyvinylpyrrolidone (PVP) for simulated materials with tissue-equivalent dielectric properties. METHODS: PVP and salt were used to control, respectively, relative permittivity and electrical conductivity in a collection of 63 samples with a range of solute concentrations. Their dielectric properties were measured with a commercial probe and fitted to a 3D polynomial in order to establish an empirical recipe. The material's thermal properties and MR spectra were measured. RESULTS: The empirical polynomial recipe (available at https://www.amri.ninds.nih.gov/cgi-bin/phantomrecipe) provides the PVP and salt concentrations required for dielectric materials with permittivity and electrical conductivity values between approximately 45 and 78, and 0.1 to 2 siemens per meter, respectively, from 50 MHz to 4.5 GHz. The second- (solute concentrations) and seventh- (frequency) order polynomial recipe provided less than 2.5% relative error between the measured and target properties. PVP side peaks in the spectra were minor and unaffected by temperature changes. CONCLUSION: PVP-based phantoms are easy to prepare and nontoxic, and their semitransparency makes air bubbles easy to identify. The polymer can be used to create simulated material with a range of dielectric properties, negligible spectral side peaks, and long T2 relaxation time, which are favorable in many MR applications. Magn Reson Med 80:413-419, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

A low-cost Mr compatible ergometer to assess post-exercise phosphocreatine recovery kinetics.

OBJECTIVE: To develop a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems to reliably quantify metabolic parameters in human lower leg muscle using phosphorus magnetic resonance spectroscopy. MATERIALS AND METHODS: We constructed an MR compatible ergometer using commercially available materials and elastic bands that provide resistance to movement. We recruited ten healthy subjects (eight men and two women, mean age ± standard deviation: 32.8 ± 6.0 years, BMI: 24.1 ± 3.9 kg/m2). All subjects were scanned on a 7 T whole-body magnet. Each subject was scanned on two visits and performed a 90 s plantar flexion exercise at 40% maximum voluntary contraction during each scan. During the first visit, each subject performed the exercise twice in order for us to estimate the intra-exam repeatability, and once during the second visit in order to estimate the inter-exam repeatability of the time constant of phosphocreatine recovery kinetics. We assessed the intra and inter-exam reliability in terms of the within-subject coefficient of variation (CV). RESULTS: We acquired reliable measurements of PCr recovery kinetics with an intra- and inter-exam CV of 7.9% and 5.7%, respectively. CONCLUSION: We constructed a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems, which allowed us to quantify reliably PCr recovery kinetics in lower leg muscle using 31P-MRS.

Heat equation inversion framework for average SAR calculation from magnetic resonance thermal imaging.

Deposition of radiofrequency (RF) energy can be quantified via electric field or temperature change measurements. Magnetic resonance imaging has been used as a tool to measure three dimensional small temperature changes associated with RF radiation exposure. When duration of RF exposure is long, conversion from temperature change to specific absorption rate (SAR) is nontrivial due to prominent heat-diffusion and conduction effects. In this work, we demonstrated a method for calculation of SAR via an inversion of the heat equation including heat-diffusion and conduction effects. This method utilizes high-resolution three dimensional magnetic resonance temperature images and measured thermal properties of the phantom to achieve accurate calculation of SAR. Accuracy of the proposed method was analyzed with respect to operating frequency of a dipole antenna and parameters used in heat equation inversion. Bioelectromagnetics. 37:493-503, 2016. © 2016 Wiley Periodicals, Inc.

Effects of Anatomical Differences on Electromagnetic Fields, SAR, and Temperature Change.

Electromagnetic field simulations are increasingly used to assure RF safety of patients during MRI exams. In practice, however, tissue property distribution of the patient being imaged is not known, but may be represented with a pre-existing model. Repeatedly, agreement in transmit magnetic (B1+) field distributions between two geometries has been used to suggest agreement in heating distributions. Here we examine relative effects of anatomical differences on B1+ distribution, Specific Absorption Rate (SAR) and temperature change (ΔT). Numerical simulations were performed for a single surface coil positioned adjacent a homogeneous phantom and bovine phantom, each with slight geometric variations, and adjacent two different human body models. Experimental demonstration was performed on a bovine phantom using MR thermometry and B1+ mapping. Simulations and experiments demonstrate that B1+ distributions in different samples can be well correlated, while notable difference in maximum SAR and ΔT occur. This work illustrates challenges associated with utilizing simulations or experiments for RF safety assurance purposes. Reliance on B1+ distributions alone for validation of simulations and/or experiments with a sample or subject for assurance of safety in another should be performed with caution.

Subject- and resource-specific monitoring and proactive management of parallel radiofrequency transmission.

PURPOSE: Develop a practical comprehensive package for proactive management of parallel radiofrequency (RF) transmission. METHODS: With a constrained optimization framework and predictive models from a prescan based multichannel calibration, we presented a method supporting design and optimization of parallel RF excitation pulses that accurately obey the forward/reflected peak and average power limits of the RF power amplifiers in parallel transmit imaging experiments and Bloch simulations. Moreover, local SAR limits were incorporated into the parallel RF excitation pulses using electromagnetic field simulations. Virtual transmit coils concept for minimization of reflected power (effecting subject-specific matching) was additionally demonstrated by leveraging experimentally calibrated power models. RESULTS: Incorporation of experimentally calibrated power prediction models resulted in accurate compliance with prescribed hardware and global specific absorption rate (SAR) limits. Incorporation of spatial average 10 g SAR models, facilitated by simplifying numerical approximations, provided assurance of patient safety. RF pulses designed with various constraints demonstrated excellent excitation fidelity-the normalized root-mean-square error of the simulated excitation profiles was 2.6% for the fully constrained pulses, comparable to that of the unconstrained pulses. An RF shimming example showed a reduction of the reflected-to-forward power ratio to 1.7% from a conventional approach's 8.1%. CONCLUSION: Using the presented RF pulse design method, effective proactive management of the multifaceted power and SAR limits was demonstrated in experimental and simulation studies. Magn Reson Med 76:20-31, 2016. © 2015 Wiley Periodicals, Inc.

A flexible nested sodium and proton coil array with wideband matching for knee cartilage MRI at 3T.

PURPOSE: We describe a 2 × 6 channel sodium/proton array for knee MRI at 3T. Multielement coil arrays are desirable because of well-known signal-to-noise ratio advantages over volume and single-element coils. However, low tissue-coil coupling that is characteristic of coils operating at low frequency can make the potential gains from a phased array difficult to realize. METHODS: The issue of low tissue-coil coupling in the developed six-channel sodium receive array was addressed by implementing 1) a mechanically flexible former to minimize the coil-to-tissue distance and reduce the overall diameter of the array and 2) a wideband matching scheme that counteracts preamplifier noise degradation caused by coil coupling and a high-quality factor. The sodium array was complemented with a nested proton array to enable standard MRI. RESULTS: The wideband matching scheme and tight-fitting mechanical design contributed to >30% central signal-to-noise ratio gain on the sodium module over a mononuclear sodium birdcage coil, and the performance of the proton module was sufficient for clinical imaging. CONCLUSION: We expect the strategies presented in this study to be generally relevant in high-density receive arrays, particularly in x-nuclei or small animal applications. Magn Reson Med 76:1325-1334, 2016. © 2015 Wiley Periodicals, Inc.

A method for safety testing of radiofrequency/microwave-emitting devices using MRI.

PURPOSE: Strict regulations are imposed on the amount of radiofrequency (RF) energy that devices can emit to prevent excessive deposition of RF energy into the body. In this study, we investigated the application of MR temperature mapping and 10-g average specific absorption rate (SAR) computation for safety evaluation of RF-emitting devices. METHODS: Quantification of the RF power deposition was shown for an MRI-compatible dipole antenna and a non-MRI-compatible mobile phone via phantom temperature change measurements. Validation of the MR temperature mapping method was demonstrated by comparison with physical temperature measurements and electromagnetic field simulations. MR temperature measurements alongside physical property measurements were used to reconstruct 10-g average SAR. RESULTS: The maximum temperature change for a dipole antenna and the maximum 10-g average SAR were 1.83°C and 12.4 W/kg, respectively, for simulations and 1.73°C and 11.9 W/kg, respectively, for experiments. The difference between MR and probe thermometry was <0.15°C. The maximum temperature change and the maximum 10-g average SAR for a cell phone radiating at maximum output for 15 min was 1.7°C and 0.54 W/kg, respectively. CONCLUSION: Information acquired using MR temperature mapping and thermal property measurements can assess RF/microwave safety with high resolution and fidelity.

Method for in situ characterization of radiofrequency heating in parallel transmit MRI.

In ultra-high-field magnetic resonance imaging, parallel radiofrequency (RF) transmission presents both opportunities and challenges for specific absorption rate management. On one hand, parallel transmission provides flexibility in tailoring electric fields in the body while facilitating magnetization profile control. On the other hand, it increases the complexity of energy deposition as well as possibly exacerbating local specific absorption rate by improper design or delivery of RF pulses. This study shows that the information needed to characterize RF heating in parallel transmission is contained within a local power correlation matrix. Building upon a calibration scheme involving a finite number of magnetic resonance thermometry measurements, this work establishes a way of estimating the local power correlation matrix. Determination of this matrix allows prediction of temperature change for an arbitrary parallel transmit RF pulse. In the case of a three transmit coil MR experiment in a phantom, determination and validation of the power correlation matrix were conducted in less than 200 min with induced temperature changes of <4°C. Further optimization and adaptation are possible, and simulations evaluating potential feasibility for in vivo use are presented. The method allows general characteristics indicative of RF coil/pulse safety determined in situ.